ROSE for Improved Molecular Marker Testing Via EBUS

Official title

Rapid Onsite Cytopathologic Evaluation for Improved Molecular Marker Testing Via Endobronchial Ultrasound Bronchoscopy - A Randomized Controlled Trial

Overview

This research study is being done to compare two ways to conduct bronchoscopic biopsy of lymph nodes and other structures in the chest (i.e. the presence or absence of an on-site cytotechnologist performing a limited microscopic evaluation to provide non-binding feedback on specimen adequacy in real time during the procedure).

Detailed description

Endobronchial ultrasound (EBUS) is a highly safe and effective bronchoscopic procedure that can achieve diagnostic yields of over 90% for lung cancer - similar to those with the more-invasive surgical mediastinoscopy - with EBUS enjoying the advantage of a near 0% complication rate in several large studies. This has led to EBUS becoming the procedure of choice for mediastinal staging of lung cancer. Increasingly, bronchoscopists are being asked to perform EBUS not only for lung cancer staging but also for tissue acquisition for molecular markers to assess for mutations that can be treated with biologic therapy. However, a frequently encountered clinical scenario is that while an EBUS is diagnostic for lung cancer, it is non-diagnostic for molecular testing because of an insufficient amount of tissue material being collected. According to multiple studies, the "molecular yield" for EBUS in lung cancer can range from 74-82%. These studies have not specifically looked at adequacy of biomarkers, which could be distinctly different considering that evaluation of biomarkers requires more tissue for next generation sequencing (NGS). Currently, Johns Hopkins Hospital uses NGS as standard of care for identifying mutations associated with malignant cells. NGS analysis, which is usually reported as a percentage of cells that express one of many biomarkers currently being tested as standard of care, is performed via immunohistochemistry (IHC), necessitating the presence of a sufficiently cellular material with \>100 tumor cells for reliable quantitative characterization. To the investigator's knowledge, the rates of NGS biomarker sufficiency have not been prospectively analyzed to date.

Rapid on-site evaluation (ROSE) is an optional step during EBUS bronchoscopy in which an on-site cytotechnologist performs a limited microscopic evaluation to provide non-binding feedback on specimen adequacy in real time during the procedure. The cytotechnologist can also aid specimen processing e.g. through creation of a "tissue clot" in addition to use of the more standard liquid-based medium. At Johns Hopkins, EBUS procedures are routinely performed both with and without ROSE since the presence or absence of ROSE during EBUS has not been shown to impact diagnostic yield or procedural safety. However, its impact on NGS biomarker sufficiency has not been tested to the investigator's knowledge.

This study aims to investigate whether ROSE can impact NGS biomarker sufficiency by assisting the bronchoscopist in obtaining adequate tissue from the appropriate site. The hypothesis is that ROSE will decrease the rate of insufficient tumor tissue to permit NGS biomarker testing.

Interventions

• Other ROSE (presence of cytotech) & liquid prep
  Standard of care EBUS will include presence of trained cytotechnologist providing on-site cytopathology feedback to bronchoscopist during the procedure. Sample is liquid.
• Other NO-ROSE (absence of cytotech) & liquid prep
  Standard of care EBUS will NOT include presence of trained cytotechnologist providing on-site cytopathology feedback to bronchoscopist during the procedure. Sample is liquid.
• Other ROSE (presence of cytotech) & tissue clot sample
  Standard of care EBUS will include presence of trained cytotechnologist providing on-site cytopathology feedback to bronchoscopist during the procedure. Sample is a tissue clot.
• Other NO-ROSE (absence of cytotech) & tissue clot sample
  Standard of care EBUS will NOT include presence of trained cytotechnologist providing on-site cytopathology feedback to bronchoscopist during the procedure. Sample is a tissue clot.

Primary outcome measures

• Percentage of NGS biomarker testing attempts [Time frame: within 60 days of procedure]

Secondary outcome measures (7)

• Level of Programmed Cell Death Protein 1 (PD-1) [Time frame: within 60 days of procedure]
• Number of targets [Time frame: During Procedure]
• Number of passes (ROSE arms only) [Time frame: During Procedure]
• Number of secondary procedures [Time frame: During Procedure]
• Need for repeat EBUS or another procedure [Time frame: Within 30 days of procedure]
• Procedure time [Time frame: During Procedure]
• Number of Procedural complications [Time frame: Within 7 days of the procedure]

Eligibility criteria

Inclusion criteria

• Inpatients or outpatients >18 years old
• Capable of informed consent
• Known or suspected non-small cell lung cancer (NSCLC)
• Referred to the interventional pulmonary team at Johns Hopkins Hospital (JHH), Johns Hopkins Bayview Medical Center (JHBMC), or other participating sites for tissue sampling of a hilar/mediastinal lymph node or another lesion accessible by convex-probe (CP) EBUS

Exclusion criteria

• Refuse participation
• Standard contraindications to EBUS and bronchoscopy in general: bleeding disorders, antiplatelet or anticoagulant usage, high fraction of inspired oxygen (FiO2) requirement, and clinical instability
• Pregnant women
• Cytotechnologist not available at the time of screening, enrollment, or randomization

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Other

Study locations

United States · 4 centers

• Northwestern Medicine — Chicago
• Johns Hopkins Bayview Medical Center — Baltimore
• Johns Hopkins Hospital — Baltimore
• The Medical University of South Carolina (MUSC) — Charleston

Publications

• Annema JT, van Meerbeeck JP, Rintoul RC, Dooms C, Deschepper E, Dekkers OM, De Leyn P, Braun J, Carroll NR, Praet M, de Ryck F, Vansteenkiste J, Vermassen F, Versteegh MI, Veselic M, Nicholson AG, Rabe KF, Tournoy KG. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. JAMA. 2010 Nov 24;304(20):2245-52. doi: 10.1001/jama.2010.1705. PMID 21098770
• Varela-Lema L, Fernandez-Villar A, Ruano-Ravina A. Effectiveness and safety of endobronchial ultrasound-transbronchial needle aspiration: a systematic review. Eur Respir J. 2009 May;33(5):1156-64. doi: 10.1183/09031936.00097908. PMID 19407050
• Anantham D, Koh MS, Ernst A. Endobronchial ultrasound. Respir Med. 2009 Oct;103(10):1406-14. doi: 10.1016/j.rmed.2009.04.010. Epub 2009 May 15. PMID 19447014
• Silvestri GA, Gonzalez AV, Jantz MA, Margolis ML, Gould MK, Tanoue LT, Harris LJ, Detterbeck FC. Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May;143(5 Suppl):e211S-e250S. doi: 10.1378/chest.12-2355. PMID 23649440
• Sakakibara R, Inamura K, Tambo Y, Ninomiya H, Kitazono S, Yanagitani N, Horiike A, Ohyanagi F, Matsuura Y, Nakao M, Mun M, Okumura S, Inase N, Nishio M, Motoi N, Ishikawa Y. EBUS-TBNA as a Promising Method for the Evaluation of Tumor PD-L1 Expression in Lung Cancer. Clin Lung Cancer. 2017 Sep;18(5):527-534.e1. doi: 10.1016/j.cllc.2016.12.002. Epub 2016 Dec 22. PMID 28111119
• Oezkan F, Khan A, Zarogoulidis P, Hohenforst-Schmidt W, Theegarten D, Yasufuku K, Nakajima T, Freitag L, Darwiche K. Efficient utilization of EBUS-TBNA samples for both diagnosis and molecular analyses. Onco Targets Ther. 2014 Nov 10;7:2061-5. doi: 10.2147/OTT.S72974. eCollection 2014. PMID 25419143
• Jurado J, Saqi A, Maxfield R, Newmark A, Lavelle M, Bacchetta M, Gorenstein L, Dovidio F, Ginsburg ME, Sonett J, Bulman W. The efficacy of EBUS-guided transbronchial needle aspiration for molecular testing in lung adenocarcinoma. Ann Thorac Surg. 2013 Oct;96(4):1196-1202. doi: 10.1016/j.athoracsur.2013.05.066. Epub 2013 Aug 21. PMID 23972930
• Yung RC, Otell S, Illei P, Clark DP, Feller-Kopman D, Yarmus L, Askin F, Gabrielson E, Li QK. Improvement of cellularity on cell block preparations using the so-called tissue coagulum clot method during endobronchial ultrasound-guided transbronchial fine-needle aspiration. Cancer Cytopathol. 2012 Jun 25;120(3):185-95. doi: 10.1002/cncy.20199. Epub 2011 Dec 5. PMID 22144401

Identifiers

NCT: NCT04945317 · IRB00162151

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗